Carica papaya L.

MALAYSIAN HERBAL MONOGRAPH

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Betik Leaves

Carica papaya L.

Caricaceae

  

fig1a fig1b
(a) (b)
fig1c fig1d
(c) (d)
 fig1e fig1f 
 (e) (f) 
fig1g fig1h
(g) (h)
Figure 1 : Carica papaya. (a) Tree; (b) stem with leaves scar; (c) adaxial leaf; (d) abaxial leaf; (e) hermaphrodite flower; (f) male flowers; (g) female flower with showy stigma; (h) unripe fruits. (Photos courtesy of Institute for Medical Research, 2016)  

   

DEFINITION

Betik leaves consist of the powder of dried leaves of Carica papaya L. (Caricaceae).

SYNONYM

Carica citriformis J.Jacq. ex Spreng., Carica hermaphrodita Blanco, Carica mamaya Vell., Carica peltata Hook. & Arn., Carica posopora L., Papaya carica Gaertn., Papaya citriformis (Jacq.) A. DC. [1]

VERNACULAR NAMES

Pawpaw, papaya (English); Betek, betik, gedang (Malay); Fan mu gua (Chinese); Pappali, pappalippal (Tamil) [2].

CHARACTER

Colour            :           Green to dark green [3]

Odour             :           Characteristic [3]

Taste              :           Bitter [3]

IDENTIFICATION

Plant Morphology

C. papaya is trees or shrubs, 2–10 m tall, containing white milky-juice in all parts. Stem cylindrical, usually unbranched, sometimes branched due to injury, hollow with prominent leaf scars and spongy-fibrous tissue, 10–30 cm in diameter. Leaves simple,spirally arranged, clustered near apex of trunk, with leaf blade orbicular, 25-75 cm in diameter, palmately and deeply 7-11-lobed, glabrous, prominently veined; petiole hollow, greenish or purplish-green, 40–100 cm long, 1–3 cm in diameter. Flowers male, female or hermaphrodite, axillary, and can be found on separate trees. Male flowers in panicles, 25-100 cm long, sessile; calyx cup-shaped, small ca. 2 mm long, 5-lobed; corolla tube creamy yellow, 3-6 cm long, 5-lobed, lanceolate, ca. 1.8 cm long, 0.45 cm wide; stamens 10, in 2 whorls alternating with the petal lobes with 5 longer and 5 shorter, shorter ones almost without filaments; filaments white, ca. 1.5 mm long, papilose; anthers 1.5–2 mm long, 2-celled dehiscing longitudinally, basifixed. Female flowers usually solitary or aggregated in few-flowered cymes, 3.5–5 cm long; pedicel short or nearly absent; calyx cup-shaped, 3–4 mm long, yellow green in colour; corolla of 5 almost free petals, creamy yellow, oblong or lanceolate, 5–6.2 long, 1.2–2 cm wide; ovary ovoid, 2–3 cm long, with numerous ovules; stigmas 5, fan-shaped, sessile, ca. 6 mm long. Hermaphrodite flowers of 2 main types: elongata type with short-peduncle clusters, petals 5 with partially united, stigmas fan-shaped, ovary elongate, stamens 10 in 2 clusters; pentandria type with short-peduncle clusters, petals 5 with almost free all along their length, stigmas fan-shaped, ovary ovoid oblong, stamens 5 attached  by long filaments near base of ovary. Fruits fleshy berry, ovoid-oblong to nearly spherical, 10–30 cm long, yellowish or orange at maturity. Seeds numerous, wrinkled, globose, 5 mm in diameter, each enclosed in gelatinous membrane, black or greyish at maturity. [3, 4, 5, 6] 

Microscopy

Powdered material consists of fragments of fibre; fragment of the parenchyma cells of the leaves, in surface view or elongated parenchyma showing some cells containing druses of calcium oxalate crystals; lower epidermis with stomata surrounded by anisocytic and actinocytic stomata; fragment of lamina, in transverse view, showing upper epidermis with spongy mesophyll cells; fragments of annular vessels. [3, 7, 8, 9]

fig2a fig2b fig2c
 (a) (b) (c)
fig2d fig2e fig2f
 (d) (f) (g)
Figure 2 : Microscopic characters of Carica papaya leaves powder of 0.355 mm size. (a) Fibre (magnification 20x); (b) elongated parenchyma cells showing druse calcium oxalate crystals (DC) (magnification 40x); (c) parenchyma cells (magnification 40x); (d) lower epidermis with anisocytic stomata (AN) and actinocytic stomata (AC) (magnification 100x); (e) fragment of mesophyll cells (M) (magnification 40x); (f) annular vessels (magnification 20x). [Scale bars: a = 100 µm; b = 50 µm; c = 10 µm; d = 50 µm; e = 50 µm; f = 20 µm]

 

Colour Tests 

Observe colour of solution after treatment with various reagents:
 

 

Sodium chloride (10%) and ferric chloride (5%)     : Green for phenolics

Thin Layer Chromatography (TLC)

Test solution : Weigh about 5.0 g of C. papaya dried leaves powder of 0.355 mm size in a vial and add 15 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Filter the solution with a filter paper and use as test solution.
Standard solution : Dissolve rutin standard (CAS no.:153-18-4) in ethanol to produce a standard concentration 0.1 mg/mL.
Stationary phase : HPTLC Glass Silica Gel 60 F254, 10 x 10 cm
Mobile phase : Ethyl acetate : water : formic acid : acetic acid; (50 : 13 : 5.5 : 5.5) (v/v/v/v)
Application :
  1. Rutin standard (S); 5 µL, as a band
  2. Ethanol extract of C. papaya dried leaves powder (L); 5 µL, as a band
Development distance : 8 cm
Drying : Air drying
Detection :

After heating at 100°C for 5 min followed by spraying with natural product reagent and polyethylene glycol 400 reagent and observe under (a) UV at 366 nm

 

Natural Product Reagent

Dissolve 1.0 g of 2-aminoethyldiphenylborinate in 200 mL of ethyl acetate

 

Polyethylene glycol 400 (PEG 400)

Dilute 10.0 g of PEG 400 in 200 mL of ethanol

 

betik tlc
Figure 3 : TLC chromatogram of rutin (S), ethanol extract of Carica papaya dried leaves powder (L) observed under (a) UV at 366 nm after derivatisation.

High Performance Liquid Chromatography (HPLC)

Test solution : Weigh about 5.0 g of C. papaya dried leaves powder of 0.355 mm size in a vial and add 15 mL of ethanol. Sonicate the mixture for 30 min at room temperature. Filter the solution with a 0.45 µm syringe filter and use as test solution.
Standard solution : Dissolve rutin standard (CAS no.:153-18-4) in ethanol to produce a standard concentration 0.1 mg/mL. 
Chromatographic system  :

Detector: UV 354 nm

Column: Symmetry, C18 column (5 µm, 100 Å, 3.9 x 150 mm)

Column oven temperature: 30°C

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Mobile phase (Gradient mode) :

Run Time

(min)

A-

Formic acid in water (0.1%)

B-

Formic acid in acetonitrile (0.1%)
0 90 10
5 90 10
20 70 30
21 5 95
24 5 95
26 90 10
30 90 10
System suitability requirements : Perform at least five replicate injections of rutin solutions (0.1 mg/mL). The requirements of the system suitability parameters as follow:
  1. Symmetry factor (As) is not more than 1.5.
  2. Percentage of relative standard deviation (RSD) of the retention time (tr) for rutin standard is not more than 2.0%.
Acceptance criteria :
  1. Retention time (tr) of rutin in the test solution is similar to the tof the standard solution.
  2. The ultraviolet (UV) spectrum of rutin in the test solution is similar to the standard solution (optional supportive data).

  

fig4a
(a)
fig4b
(b)
Figure 4 : Whole HPLC chromatogram of (a) rutin standard solution (0.1 mg/mL) at tr  = 13.416 min and (b) ethanol extract of Carica papaya dried leaves powder showing peak corresponding to rutin standard solution at tr  = 13.402 min. 

  

fig5a
(a)
fig5b
(b)
Figure 5 : HPLC chromatogram highlighting the elution region of rutin in (a) rutin standard solution (0.1 mg/mL) and (b) ethanol extract of Carica papaya dried leaves powder showing peak corresponding to rutin standard solution at t= 13.402 min. 

 

 fig6
Figure 6 : UV spectrum of rutin standard solution (0.1 mg/mL) and ethanol extract of Carica papaya dried leaves powder.

PURITY TESTS

The purity tests are based on C. papaya dried leaves powder of 0.355 mm particle size.

Foreign Matter
Not more than 2%

 

Ash Contents
Total ash : Not more than 15%
Acid-insoluble ash : Not more than 2%

 

Loss on Drying
Not more than 8%

 

                                                                                         

   

Extractive  Values   
Water-Soluble extracts   
Hot Method  Not less than 33%
Cold Method  Not less than 6 % 
Ethanol-soluble extracts   
Hot Method    Not less than 10% 
 Cold Method Not less than 5 %


SAFETY TESTS

The safety tests are based on C. papaya dried leaves powder of 0.355 mm particle size.

Heavy Metals
Arsenic                       
: Not more than 5.0 mg/kg
Mercury : Not more than 0.5 mg/kg
Lead : Not more than 10.0 mg/kg
Cadmium : Not more than 0.3 mg/kg

 

   Microbial Limits
Total aerobic microbial count  Not more than 10cfu/g
Total yeast and mould count  Not more than 10cfu/g
 Bile-tolerant gram negative bacteria  Not more than 10cfu/g

 

Specific Pathogens
Salmonella spp. Absent in 25 g 
Escherichia coli Absent in 1 g
Staphylococcus aureus Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g

 

CHEMICAL CONSTITUENTS

Water extract of the C. papaya leaves was found to contain alkaloid carpaine [10].

Aqueous methanol extract of the C. papaya leaves was found to contain flavonoids (e.g. quercetin-3-O-rutinoside, quercetin-3-O-glucopyranuronide, quercetin-3-O-α-1C4-rhamnopyranoside, kaempferol, quercetin, apigenin), phenolic acids (e.g., protocatechuic acid, p-coumaric acid, 5,7-dimethoxycoumarin, caffeic acid, chlorogenic acid) and a cyanogenic glucoside [e.g. (R)-2-(β-D-glucopyranosyloxy)-2-phenylacetonitrile (prunasin)]. [11, 12, 13, 14, 15]

Aqueous ethanol extract of the C. papaya leaves was found to contain alkaloids (e.g. carpaine, dehydrocarpaine I, dehydrocarpaine II) [16].

Methanol extract of the C. papaya leaves was found to contain alkaloids (e.g. choline, carpamic acid, methyl carpamate, carpaine, 6-(8-methoxy-8-oxooctyl)-2-methylpiperidin-3-yl-8-(5-hydroxy-6-methylpiperidin-2-yl)octonoate,  13,26-dimethyl-2,15-dioxa-12,25-diazatricyclo[22.2.2.211,14]triacontane-3,16-dione), flavonoids (e.g. hesperidin, rutin, naringenin kaempferol, apigenin, manghaslin, clitorin, rutin, nicotifluorin), phenolic acids (e.g. chlorogenic acid, naringenin, caffeic acid, cinnamic acid, protocatechuic acid, vanillic acid, coumaric acid), amino acids (e.g. leucine, valine, alanine, glutamic acid, glutamine, aspartic acid, cysteine, phenylalanine, serine, tyrosine, histidine, tryptophan, GABA) carbohydrates (e.g. raffinose, α-glucose, β-glucose, sucrose), organic acids (e.g. propionic acid, lactic acid, quinic acid, acetic acid, malic acid, citric acid, succinic acid, fumaric acid) and others (e.g. creatine, choline, trigonelline). [17, 18, 19]

Chloroform extract of the C. papaya leaves was found to contain alkaloid (e.g. carpaine) [17].

The juice of the C. papaya leaves was found to contain alkaloid (e.g. carpaine), flavonoids (e.g. manghaslin, clitorin, rutin, nicotiflorin) and organic acids (e.g. quinic acid, malic acid and malic acid derivatives caffeoyl malate, p-coumaroyl malate and feruloyl malate) [20].

The fresh leaves of C. papaya was found to contain vitamins (e.g. ascorbic acid, thiamine, riboflavin) [21].

Lyophilized of the C. papaya leaves was found to contain phenolic acid (e.g. chlorogenic acid, caffeic acid, ferulic acid), vitamin (e.g. ascorbic acid) and a carotenoid (e.g. β-carotene) [12].

C. papaya leaves was found to contain minerals (e.g. calcium, magnesium, manganese, iron, potassium, sodium) [21].

MEDICINAL USES

Uses described in folk medicine, not supported by experimental or clinical data

C. papaya leaves in decoction or infusion is consumed orally to reduce blood pressure, blood sugar level and body fat [22, 23]. The juice of C. papaya leaves is used for irregular menstruation while infusion of young leaves is used for fever [24]. 

Biological and pharmacological activities supported by experimental data

Antidiabetic activity

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) administered orally to streptozotocin-induced diabetic male Wistar rats (250 – 300 g, 10-11 weeks old) for duration of 30 days significantly (p < 0.05) decreased the serum glucose level to 305.4 ± 9.68 mg/dL, 306.5 ± 8.8 mg/dL and 250 ± 10.2 mg/dL respectively compared to untreated diabetic rats (434 ± 7.49 mg/dL) [25].

Alcohol (30%) extract of C. papaya leaves (100, 200 and 400 mg/kg) was administered orally to alloxan-induced diabetic male and female Wistar albino rats (150 – 200 g) with blood glucose level more than 250 mg/dL for a duration of 21 days. The extract significantly (p < 0.01) reduced serum glucose level to 269.3 ± 4.9 mg/dL, 221.4 ± 4.3 mg/dL and 151.6 ± 2.6 mg/dL at respective concentration compared to glibenclamide (0.1 mg/kg) treated group (95.5 ± 1.4 mg/dL). [26]

 

 

Hypolipidemic activity

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) administered orally to streptozotocin-induced diabetic male Wistar rats (250 – 300 g, 10-11 weeks old) for duration of 30 days significantly (p < 0.05) decreased serum cholesterol level to 70.32 ± 3.27 mg/dL, 88.11 ± 4.56 mg/dL and 57.37 ± 2.9 mg/dL at respective concentration compared to untreated diabetic control group (75.62 ± 2.9 mg/dL) [25].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also significantly (p < 0.05) decreased triglyceride level to 146.5 ± 8.9 mg/dL, 144.5 ± 11.6 mg/dL and 93.71 ± 17.2 mg/dL at respective concentration compared to untreated diabetic control (232.1 ± 17.3 mg/dL) [25].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also showed significant (p < 0.05) decrease in liver cholesterol level to 11.23 ± 1.04 mg/g tissue, 10.54 ± 1.11 mg/g tissue and 9.49 ± 0.82 mg/g tissue at respective concentration compared to untreated diabetic control (10.78 ± 1.06 mg/g tissue) [25].

Aqueous extract of C. papaya leaves (0.75, 1.5 and 3 g/100 mL) also showed significant (p < 0.05) decrease in liver triglyceride level to 55.40 ± 4.64 mg/g tissue, 59.07 ± 6.48 mg/g tissue and 56.47 ± 2.43 mg/g tissue at respective concentration compared to untreated diabetic control group (69.71 ± 5.00 mg/g tissue) [25].

Alcohol (30%) extract of C. papaya leaves (400 mg/kg) administered orally to alloxan-induced diabetic male and female Wistar albino rats (150 – 200 g) for duration of 21 days significantly (p < 0.05) reduced cholesterol level (135.32 ± 4.04 mg/dL) compared to untreated diabetic control group (153.88 ± 4.19 mg/dL). The extract also significantly (p < 0.05) reduced triglyceride level (145.18 ± 3.67 mg/dL) compared to untreated diabetic control (189.86 ± 1.74 mg/dL). [26]

 

Antioxidant activity

Aqueous methanol (80%) extract of C. papaya leaves showed antioxidant activity with 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity (IC50 of 80 µg/mL) compared to L-ascorbic acid (IC50 of 4.4 µg/mL) using DPPH scavenging assay and ethylenediaminetetraacetic acid (IC50 of 9.6 µg/mL) using metal chelating assay and reducing power assay [27].

Methanol extract of C. papaya leaves (2.00 mg/mL) showed antioxidant activity with hydroxyl scavenging activity (88%), hydrogen peroxide scavenging activity (45%), metal chelating activity (38%) and reducing ability (95%) compared to ascorbic acid (0.5 mg/mL) (hydroxyl scavenging activity: 90%, hydrogen peroxide scavenging activity: 50%, metal chelating activity: 60%, reducing ability: 97%) [28].

The extract (0.25, 0.50, 1.00 and 2.00 mg/mL) also inhibited erythrocyte haemolysis with IC50 of 7.90 ± 0.06 mg/mL, 8.45 ± 0.23 mg/mL, 9.18 ± 0.17 mg/mL and 15.70 ± 0.53 mg/mL at respective concentration compared to ascorbic acid (estimated IC50 = 1.87 mg/mL). The extract (0.25, 0.50, 1.00 and 2.00 mg/mL) also inhibited erythrocyte lipid peroxidation with IC50 of 10.95 ± 1.16 mg/mL, 24.54 ± 1.47 mg/mL, 36.87 ± 0.66 mg/mL and 58.99 ± 0.34 mg/mL at respective concentration compared to ascorbic acid (estimated IC50 = 0.43 mg/mL). [28]

Fractions (petroleum ether, ethyl acetate, n-butanol and water) of ethanolic extract of C. papaya leaf (3 – 50 µg/mL) showed reactive oxygen species (ROS) scavenging activity using Dichloro-dihydro-fluorescein assay. Petroleum ether fraction (25 µg/mL) showed highest lactate dehydrogenase (LDH) leakage protection (90%) in comparison to tert-butyl hydroperoxide-treated group using LDH leakage assay. Petroleum ether fraction (25 µg/mL) showed higher reduction (47%) of ROS when compared with α-tocopherol (17%). [29]

 

Gastroprotective activity

Aqueous extract of C. papaya leaves (500 mg/kg) was administered orally to adult male Sprague Dawley rats (180 – 220 g) 30 min before induction of gastric ulcer using ethanol. The extract significantly (p < 0.05) increased glutathione peroxidase level (GPx: 2.475 ± 0.214 U/mg protein) compared to ethanol-induced untreated control group (GPx: 2.229 ± 0.281 U/mg protein). The extract reduced mean ulcer index of 993.6 ± 141.384 mm2 compared to ethanol-induced untreated control group (mean ulcer index = 6235.2 ± 386.33 mm2). [30]

 

Antimutagenic activity

Ethanol (96%) extract of C. papaya leaves (500 mg/kg) administered orally to female Wistar-Kyoto rats (100 – 250 g, four months old) for duration of 24 hr significantly (p < 0.05) decreased micronucleated polychromatic erythrocytes rate (MN-PCE: 1.6 ± 0.5) compared to cyclophosphamide (40 mg/kg) treated control group (MN-PCE: 20 ± 4.9) [31].

 

Antisickling activity

Methanol extract (75%) of C. papaya leaves (5 mg/mL) was administered to sickle erythrocytes before induction of sickling using sodium metabisulphite (2%). The extract inhibited formation of sickle cells (SS) with 0 – 2% sickle cells formation at 40 min compared to untreated SS cells (60% sickle cells formation). The extract (3 mg/mL in 0.25% sodium chloride) decreased the percentage haemolysis of SS cells to 5% compared to untreated SS cells (50%). [32]

 

Wound healing activity

Aqueous extract of C. papaya leaves (50 mg/g Vaseline and 100 mg/g Vaseline) was applied topically twice a day on dorsal neck excised wound of adult male Sprague Dawley rats (180 – 200 g). The extract showed significant (p < 0.05) decrease in healing time 12.83 ± 0.31 days and 12.33 ± 0.42 days respectively compared to 100% pure Vaseline treated control group (17.33 ± 0.67 days). [33]

 

Antibacterial activity

Ethanol extract of C. papaya leaves (100 g/100 mL) showed inhibited growth of Escherichia coli (inhibition zone = 8.30 ± 0.26 mm), Micrococcus luteus (8.23 ± 0.25 mm), Pseudomonas aeruginosa (8.23 ± 0.21 mm), Bacillus cereus (9.20 ± 0.26 mm), Klebsiella pneumonia (6.17 ± 0.15 mm) and Staphylococcus aureus (8.20 ± 0.20 mm) compared to ciprofloxacin (10 µg/mL) (E. coli = 23.50 ± 0.50 mm, M. luteus = 16.97 ± 0.45 mm, P. aeruginosa (25.0 ± 0.50 mm), B. cereus (21.83 ± 0.29 mm), K. pneumonia (14.83 ± 0.29 mm) and S. aureus (29.83 ± 0.76 mm) using well diffusion method [34]. 

 

Antifungal activity

Ethanol extract of C. papaya leaves (100 g/100 mL) showed inhibited growth of  Aspergillus niger (inhibition zone = 7.07 ± 0.12 mm), Aspergillus flavus (6.20 ± 0.20 mm), Candida  albicans (8.23 ± 0.25 mm), Candida tropicalis (10.0 ± 0.20 mm), Cryptococcus neoformans (7.0 ± 0.20 mm) and Candida kefyr (6.0 ± 0.00 mm) compared to ketoconazole (10 µg/mL) (A. niger = 7.40 ± 0.53 mm, A. flavus = 8.23 ± 0.25 mm, C. albicans = 8.83 ± 0.29 mm, C. tropicalis = 10.10 ± 0.36 mm, C. neoformans = 13.17 ± 0.29 mm and C. kefyr = 11.17 ± 0.29 mm) using well diffusion method [34]. 

 

Antimalarial activity

Methanol (70%) extract of C. papaya leaves (200 mg/kg) was administered to adult Swiss albino mice (20 g) for a duration of five days after 72 hr malaria-induction using Plasmodium berghei. The extract showed a significant (p < 0.05) reduction in parasitemia level from Day-1 post treatment (66%) to Day-5 post treatment (12%) compared to untreated control (Day-1 post treatment: 66%, Day-5 post treatment: 80%). The extract also significantly (p < 0.05) increase the percentage of chemo suppression (0.78 ± 0.04% – 82.22 ± 2.51%) compared to artesunate (3.43 ± 0.21% – 96.60 ± 2.77%) and Alstonia broonai (1.25 ± 0.09% – 53.73 ± 2.13%). [35]

 

Antiplasmodial activity

Ethanol extract of C. papaya leaves (25, 50, 100 and 150 µg/mL) showed antiplasmodial activity against chloroquine (CQ) sensitive strain of Plasmodium falciparum with IC50 of 40.8 ± 3.6%, 36.5 ± 3.6%, 25.3 ± 1.0%  and 18.0 ± 1.7% at respective concentration compared to chloroquine control group (IC50 = 1.0 ± 0.3%). [36]

Ethanol extract of C. papaya leaves (25, 50, 100 and 150 µg/mL) also inhibited the growth of CQ - resistant strain of P. falciparum with IC50 of 50.2 ± 1.0%, 32.5 ± 2.0%, 21.4 ± 2.6% and 23.1 ± 2.6% at respective concentration compared to chloroquine control group (IC50 = 5.0 ± 0.8%) using in-vitro antiplasmodial assay [36]. 

 

Platelet enhancing activity

Aqueous extract of C. papaya leaves (400 and 800 mg/kg) was administered to cyclophosphamide-induced thrombocytopenic male and female Wistar rats (100 – 125 g) for a duration of 15 days. The extract significantly (p < 0.001) increased the platelet count (400 mg/kg: 556833 ± 30414 cells/mm3, 800 mg/kg: 831000 ± 16118 cells/mm3) compared to cyclophosphamide (50 mg/kg) treated control for a duration of three days (164500 ± 13304 cells/mm3). [37]

Petroleum extract (200 mg/kg), ethyl acetate extract (200 mg/kg) and alkaloid fraction (carpaine) (2 mg/kg) of C. papaya leaves were administered subcutaneously to bulsufan-induced thrombocytopenia male Wistar rats (200 – 250 g) for a duration of 20 days increased platelet count to 662.25 ± 33.12 x 109 /L, 584.02 ± 29.20 x 109 /L and 555.5 ± 27.77 x 109 /L respectively compared to non-treated control group (78.00x 109 /L) [10].

 

Anti-inflammatory activity

Juice extract of C. papaya leaves (0.36 mL/100g and 0.72 mL/100g) was administered to male and female adult Wistar rats with hydroxyurea induced thrombocytopenia one hr before induction of paw edema into the sub-plantar surface of the right hind paw using carrageenan. At four hr of post-injection, the extract significantly inhibited paw edema swelling (p < 0.05) (43%) and (p < 0.01) (37%) at respective concentration, compared to distilled water treated control group (62%). [38]

 

Trypanostatic activity

Aqueous extract of C. papaya leaves (0.078 – 10 mg/mL) significantly (p < 0.05) reduced Trypanosoma brucei parasite count minutes post inoculation from 0.61 ± 0.04 x 106 (at lowest concentration) to 0 (at highest concentration) compared to phosphate buffered glucose solution treated control group (1.89 ± 0.06 x 106)at 30 min [39].

Aqueous extract of C. papaya leaves (0.078 – 2.5 mg/mL) significantly (p < 0.05) increased Trypanosoma brucei percentage inhibition minutes post inoculation from 67.66 ± 2.88% (at lowest concentration) to 99.22 ± 1.22% (at highest concentration) compared to control phosphate buffered glucose solution (0%) at 30 min [39].

Clinical studies

Platelet enhancing activity

A case report to study effect of C. papaya leaves extracts as compared to broad spectrum antibiotics and antimalarial drugs for five days was carried out. This case report involved a 45-year old male patient diagnosed with dengue fever with symptoms of body ache, breathing problem, shivering, vomiting and hypertension. The patient was administered with grinded C. papaya leaves mixed with some sucrose administered orally (25 mL) twice daily for five consecutive days. The observations were made on the patient’s platelet count every 24 hr before and after extract administration. Results showed recovery of platelet counts, white blood cells and neutrophils to its normal levels [40].

A pilot study on the beneficial effects of C. papaya leaf extract in combination with antiemetic, paracetamol and antibiotics on 12 patients (adult and children below 10 years old) with strong clinical suspicion of dengue, more than 3 days fever, more than 5 years of age and platelet count of above 130000 per cu.mm. The patients were administered orally with C. papaya leaf extract crushed into juice form at 8-hr interval for adults (two 5 mL doses) and children (two 2.5 mL doses) for nine consecutive days. The observations were made by taking blood sample every 24 hr to determine platelet count and other parameters. Results showed that platelet counts and total white cells increased within 24 hr of C. papaya leaf extract administration [41].

A randomized controlled trial involving 80 subjects was conducted to study the effects of C. papaya leaves extract capsules (CPC) (550 mg) to dengue fever patient. The intervention group was given additional two CPC three times daily while the control group received standard treatment. Blood samples were obtained twice daily and the platelet count and hematocrit level were determined. The result showed that CPC had significantly (p < 0.05) increased the platelet count to 200 x 103 /µL on the 9th examination compared to control group (117.48 103 /µL). No side effect was observed. Changes in haematocrit level were not significant between intervention and control group. [42]

An open labeled randomized controlled trial to study the platelet increasing effect of C. papaya leaves juice was conducted involving 290 patients (including dropouts of 62 patients) who were diagnosed with Dengue fever or Dengue haemorrhagic fever Grade I and II with platelet count of ≤ 100,000/µL. These patients were divided into two groups: one group was given standard management according to National Clinical Practice Guidelines for the Management of Dengue (control group) and another group was given fresh juice of C. papaya leaves (50 mg) concurrently with standard management (intervention group). Intervention group was treated orally at 15 min after breakfast once daily for three consecutive days. At 48th hr, the mean platelets count (MPT) significantly (p < 0.05) increased in the intervention group (mean difference of -16.76) compared to MPT at 8th hr. [43]

A non-randomized trial to study the platelet enhancing activity of C. papaya leaves was conducted involving 9 patients infected with dengue. These patients were orally given 5 mL of papaya leaf extract (3 doses daily at a 6 hr interval) for five consecutive days. No dropout was reported. The mean platelet count significantly (p < 0.05) increased from 0.618 ± 0.087 on Day 1 to 1.330 ± 0.110 on Day 6. [44]

Immunomodulatory activity

A non-randomized trial to study the immunomodulatory activity of C. papaya leaves was conducted involving 9 patients infected with dengue. These patients were orally given 5 mL of papaya leaf extract (3 doses daily at a 6 hr interval) for five consecutive days. No dropout was reported. The mean total white blood cell count significantly (p < 0.05) increased from 4911.110 ± 869.298 on Day 1 to 13100.000 ± 2000.000 on Day 6. [44]

SAFETY INFORMATION

Preclinical studies (Toxicology studies)

24-hours toxicity study

Aqueous extract of C. papaya leaves (100 – 5000 mg/kg) given orally to male Sprague-Dawley rats (180 – 250 g) for 24 hr showed no signs of toxicity at LD50 > 5000 mg/kg [45].

Aqueous extract of C. papaya leaves (100 – 800 mg/kg) given intraperitoneally to albino rats for 24 hr showed clinical signs of sluggishness, awkward posture, loss of appetite, starry hair coat and terminal death at median LD50 > 600 mg/kg [39].

14-days toxicity study

Aqueous extract of C. papaya dried leaf (2000 mg/kg) was administered orally as a single dose to female Sprague Dawley rats (aged between 6 to 7 weeks old). There was no toxicity effect observed for a period of 14 days (LD50 > 2000 mg/kg). [40]

Aqueous extract of C. papaya leaves (10 – 500 mg/kg) given orally to male Sprague-Dawley rats (180 – 250 g) for 14 days showed dose-dependent increase in levels of alkaline phosphatase (AP), gamma glutamyl transferase (GGT) and bilirubin (BIL) suggesting toxicity to the hepato-billiary system [45].

Aqueous extract of C. papaya leaves (10 – 500 mg/kg) given orally to male Sprague-Dawley rats (170 – 190 g) g) for 14 days showed significant reduction in sperm count, sperm motility (conc: 500 mg/kg; p < 0.01), sperm viability (conc: 100 – 500 mg/kg; p < 0.001) and testosterone (conc: 100 – 500 mg/kg; p < 0.01) [45].

28-days toxicity study

Aqueous extract of C. papaya leaf powdered (2000 mg/kg) was administered orally to both male and female Sprague Dawley rats (aged between six to seven weeks) once daily for 28 days. The extract did not cause any mortality and abnormalities on the behavior or physical changes as well as hematological parameters and serum biochemistry. [20]

13-weeks toxicity study

Aqueous extract of C. papaya leaf (2000 mg/kg) was administered orally by oral gavage to both male and female Sprague Dawley rats (aged between six to seven weeks) for duration of 13 weeks. The extract did not cause any mortality and abnormalities of behavior or changes in body weight as well as food and water intake. However, significant (p < 0.05) differences was observed for biochemistry values (LDH, creatinine, total protein and albumin) which require further hepatotoxicity study. The No Observed Adverse Effect Level (NOAEL) was 2000 mg/kg. [46]

Others (Adverse reaction, contraindication, side effect, warning, precaution)

Information and data have not been established.

DOSAGE

Information and data have not been established.

STORAGE

Store below 30°C. Protect from light and moisture.

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